Elevated levels of TNF play an important role in pathologic inflammation. TNF also referred to as (TNFα) has been implicated in the pathophysiology of a variety of human diseases and disorders, including sepsis, infections, autoimmune diseases, transplant rejection and graft-versus-host disease (see e.g., Moeller et al. (1990) Cytokine 2:162; U.S. Pat. No. 5,231,024 to Moeller et al.; European Patent Publication No. 260 610 B1 by Moeller, A. et al.; Vasilli (1992) Annu. Rev. Immunol. 10:411; Tracey and Cerami (1994) Annu. Rev. Med. 45:491).
Ankylosing spondylitis (AS) which has been associated with elevated levels of TNF (Lange et al. (2000) Eur J Med. Res. 5(12):507), and is a common inflammatory rheumatic disease that produces progressive spinal stiffness and restriction of mobility. AS is a form of chronic inflammation of the spine and the sacroiliac joints, which can cause pain and stiffness in and around the spine. Over time, chronic spinal inflammation (spondylitis) can lead to a complete cementing together (fusion) of the vertebrae, a process referred to as ankylosis, which, in turn, can lead to loss of mobility of the spine
AS is often diagnosed using a combination of methods, including examining symptoms, physical examination, and x-ray analysis. An AS patient's symptoms may include pain and morning stiffness of the spine and sacral areas with or without accompanying inflammation in other joints, tendons, and organs. Early symptoms of AS can be very deceptive, however, as stiffness and pain in the low back can be seen in many other conditions, and, as a result, time may pass before the diagnosis of AS is even considered. In addition, physical examination of the patient may reveal signs of inflammation and decreased range of motion of joints, often particularly apparent in the spine. Flexibility of the low back and/or neck may be decreased. Further clues to the diagnosis may be suggested by x-ray abnormalities of the spine, or the presence of the blood test genetic marker, the HLA-B27 gene.
Structural damage is associated with AS, and results from degradation and resorption in cartilage and bone of the joint, resulting in joint destruction. Therapeutically, it is important to address both the symptoms of the patient having AS, as well as the structural damage caused by joint destruction associated with the disease.
Traditional treatment of AS has included administering nonsteroidal antiinflammatory drugs (NSAIDs) to the patient to decrease pain and stiffness of the spine and other joints. Commonly used NSAIDs include indomethacin (Indocin), tolmetin (Tolectin), sulindac (Clinoril), naproxen (Naprosyn), and diclofenac (Voltaren). More recently, anti-TNF biologic agents, such as etanercept, infliximab, and adalimumab, have been shown to be effective at reducing symptoms associated with AS.